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Intracellular Trafficking of the Amyloid beta-Protein Precursor (APP) Regulated by Novel Function of X11-Like

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Title: Intracellular Trafficking of the Amyloid beta-Protein Precursor (APP) Regulated by Novel Function of X11-Like
Authors: Saito, Yuhki Browse this author →KAKEN DB
Akiyama, Mayu Browse this author
Araki, Yoichi Browse this author
Sumioka, Akio Browse this author
Shiono, Maki Browse this author
Taru, Hidenori Browse this author →KAKEN DB
Nakaya, Tadashi Browse this author
Yamamoto, Tohru Browse this author →KAKEN DB
Suzuki, Toshiharu Browse this author →KAKEN DB
Issue Date: 19-Jul-2011
Publisher: The Public Library of Science
Journal Title: PLOS ONE
Volume: 6
Issue: 7
Start Page: e22108
Publisher DOI: 10.1371/journal.pone.0022108
PMID: 21818298
Abstract: Background: Amyloid beta (A beta), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid beta-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by alpha- or beta-, and gamma-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of A beta lowers. X11L expresses another function in the regulation of intracellular APP trafficking. Methodology: In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP. Conclusions: X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Ab generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 利治

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